A number of normal cell types have been found to possess on their surfaces unique major external proteins which regularly become deleted following malignant transformation. One of these proteins, recently isolated from contact-inhibited hamster melanocytes, has been found, for the first time, to restore to malignant melanocytes the property of contact inhibition of growth (density-dependent inhibition of cell division). Its range of activity transcends both species and tissue barriers, and it has been found to be particularly effective with respect to human colon carcinoma, strikingly inhibiting growth in vitro in the absence of toxicity, at microgram concentrations even lower than required for melanocytes. This newly identified contact-inhibitory factor may be the prototype for a fundamental regulatory mechanism for control of normal mammalian cell interactions. It is proposed to study with respect to a wide spectrum of human colon carcinomas, the range of activity of the contact-inhibitory factor as well as its chemical characterization and mechanisms of action. The relation of this protein to the surface proteins of normal colon cells will also be studied. The proposed studies will provide a rational basis for possible eventual control of human colon carcinoma by restoration of deleted cell surface components participating in feedback mechanisms required for normal growth control.